In the absence of an effective vaccine or therapy, the incidence of acquired immune deficiency syndrome (AIDS) in the United States and other countries is likely to increase during the next few years. Preventing infection with the human immunodeficiency virus (HIV) will depend upon education and counselling to prevent transmission among the populations at risk for AIDS.
Recently, the initial events in infection of human T lymphocytes, macrophages, and other cells by HIV have been elucidated These events involve the attachment of the HIV envelope glycoprotein gp120 to its cellular receptor, CD4. Cells that lack CD4 are not susceptible to HIV infection, but become susceptible after they are transfected with the CD4 gene and express CD4 on their surfaces This information has led to studies of the use of recombinant CD4 (rCD4) which might be used therapeutically to block the CD4-binding sites on HIV, preventing it from binding to CD4 on host cells. However, this would provide only a passive blockage of virus infection, and would not lead to active elimination of the virus.
A therapeutic approach has been developed to eliminate the virus. This involves linkage of CD4 to the Fc region of human IgG. Capon et al. Nature 337:525 (1989). The Fc region of human IgG is the natural ligand for receptors on monocytic cells. Moreover, in the Fc portion of IgG reside immunoglobulin functions such as Fc receptor binding, protein A binding and complement fixation. These properties of the Fc portion of human immunoglobulin are the major mechanisms for elimination of pathogens. Fc activates the complement pathway, resulting in lysis of the pathogen, whereas binding to the Fc receptors on effector cells can lead to ingestion of the pathogen by phagocytosis or lysis by killer cells.
Nevertheless, the vast amount and diversity of natural antibodies (i.e. non-HIV specific IgG) found in vivo remains a major obstacle to this kind of in vivo therapy since non-HIV specific IgG would be expected to block binding of the Fc region with Fc receptors. A need exists to develop a therapeutic modality that overcomes these problems.